IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease.

The variety of clinical presentations in IgG4-related disease in Rheumatology

The variety of clinical presentations in IgG4‑related disease in Rheumatology
Agata Sebastian 0 1 2 4
Maciej Sebastian 0 1 2 4
Maria Misterska‑Skóra 0 1 2 4
Piotr Donizy 0 1 2 4
Agnieszka Hałoń 0 1 2 4
Arkadiusz Chlebicki 0 1 2 4
Artur Lipiński 0 1 2 4
Piotr Wiland 0 1 2 4
0 Division of Pathomorphology and Clinical Cytology, Department of Pathomorphology, Wroclaw Medical University , Borowska 213, 50-556 Wroclaw , Poland
1 Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical Hospital , Borowska 213, 50-556 Wroclaw , Poland
2 Department of Rheumatology and Internal Medicine, Wroclaw Medical Hospital , Borowska 213, 50-556 Wroclaw , Poland
3 Agata Sebastian
4 Department of Rheumatology and Internal Medicine, Wroclaw Medical University , Borowska 213, 50-556 Wroclaw , Poland
IgG4-related disease (IgG4-RD) belongs to the group of rare diseases in which the identification of the characteristic histology and immunohistochemistry provides with the gold standard in the diagnosis. The variable organ dysfunction reflects the clinical presentation. The examples of different IgG4-RD presentations in the Rheumatology Unit were discussed in this article. The spectrum of IgG4-RD is wide-ranging and manifested in one or more organs synchronously or metachronously. In the presented article, we described five different cases of IgG4-RD. Four cases were reaffirmed in the histopathological assessment. The clinical and laboratory findings were analyzed and the assigned therapy was discussed. According to our experience, the diagnosis of IgG4-RD requires the careful clinicopathological correlation. The diagnosis relies on the coexistence of various clinical, laboratory, radiological, and histopathological findings, although none of them is pathognomonic itself. The time needed for the diagnosis and variety of clinical forms of IgG4-RD shows that there is need of the cooperation among many specialists for the better and earlier recognition of the disease.
IgG4; Treatment; Differential diagnosis; Pathology
Introduction
The IgG4-related disease (IgG4-RD) is a chronic,
inflammatory, multi-organ, systemic disease [
1
]. The name was first
proposed by the Japanese investigators in 2010 [
2
], and the
comprehensive diagnostic criteria for the IgG4-RD were first
determined and unified by Umehara et al. in 2011 [
3
]. The
disease can affect many organs: most commonly the
pancreas, liver, bile ducts, thyroid gland, aorta, retroperitoneum,
lymph nodes, lacrimal glands, and occasionally the brain [
4
].
The variable organ dysfunction reflects the clinical
presentation. Patients may be asymptomatic and only incidentally
diagnosed at the physical examination or imaging. They
may present a single or multiple organ involvement. The
histopathological assessment is the diagnostic gold standard,
hallmarked by the lymphoplasmacytic infiltrates of
IgG4plasma cells, the storiform fibrosis, tissue eosinophilia, and
the obliterative phlebitis. Large epidemiologic studies are
lacking. The exact frequency of IgG4-RD in Europe is still
unknown. The prevalence of IgG4-RD in the Rheumatology
Units is low, the diagnostic process is time-consuming, it
may mimic other diseases and there is need for the specific
histological assessment.
This article gives examples of different IgG4-RD
presentations in the Rheumatology Unit in Eastern Europe.
Materials and methods
The patients were diagnosed with IgG4-RD in the
Rheumatology and the Internal Medicine Department between 2014
and 2016. The data were collected retrospectively. The
inclusion criteria were: age >18 years and the histopathological
picture of IgG4-RD. The data included the time from the first
symptoms to the establishment of IgG4-RD diagnosis, the
age and gender of patients, the localization of lesions,
histopathological biopsies, IgG4, IgG, and IgM concentration in
blood samples, the erythrocyte sedimentation rate (ESR) and
C-reactive protein (CRP) values, C3 and C4 values treated
with and the responsiveness to corticosteroids (CS), and the
history of the atopic disease. Patients with the different
IgG4RD presentations were chosen to illustrate the complexity of
IgG4-RD cases treated in the Rheumatology Unit. We
performed the literature review following the methods specified
by Gasparyan et al. [
5
]. The searches were conducted in the
PubMed (part of the National Library of Medical Databases)
and Cochrane Library. The search strategy was based on the
publication since 2010. The key word included: IgG4 related
disease or IgG4 or autoimmune pancreatitis or Mikulicz
disease. Authors analyzed the review articles and case reports.
Results
Five cases of IgG4-RD were diagnosed. Four cases were
reaffirmed in the histopathological assessment (Fig. 1).
The main localization of IgG4-RD was the salivary glands
(four cases). In two cases, the lacrimal gland enlargement
was the first presentation of IgG4-RD (Fig. 2). In one
case, it was the unilateral submandibular gland
enlargement with the granulomatosis and polyangiitis (GPA)
found in the biopsy. In case number four the pancreatitis
was the first clinical presentation of IgG4-RD. The
suspicion of IgG4-RD was made due to the increased IgG4
serum concentration, eosinophilia, concomitant parotid,
the submandibular glands enlargement, peripheral
lymphadenopathy, and the lack of specific antibodies, e.g.,
antinuclear antibodies. In case number five, the clinical
presentation included the lacrimal enlargement, peripheral
lymphadenopathy, and the clinical signs of ileus (Fig. 3).
The characteristics of the clinical symptoms of the
disease are demonstrated in Table 1 and Figs. 2, 3. None of
the patients had the positive symptoms of dryness or the
allergy history. Antinuclear antibodies (ANA) were
positive only in case number one, but in a very low titer. The
hypocomplementemia C3 and C4 were observed in case
number three, where IgG4-RD and GPA were diagnosed.
Three patients had the elevated blood IgG4
concentration, but not IgG fraction except case number three. In this
case, the IgG4 fraction was not assessed because
IgG4RD was not suspected at the beginning of the
diagnostic process. In the cases with the lacrimal gland
enlargement, the IgM fraction in the serum was decreased. ESR
and CRP concentrations were elevated in two patients.
The laboratory findings of the patients with IgG4-RD are
Fig. 1 The lacrimal gland
with the dense
lymphoplasmacytic infiltration and
advanced fibrosis, which are
highly histologically
suggestive for IgG4-related disease
(a 200×, H&E staining). The
inflammatory infiltration in the
presented above lacrimal gland
is predominantly consisted
of the IgG4-positive plasma
cells (b 200×, hematoxylin).
Immunostaining for the IgG4 in
the salivary gland in one
highpower field (hpf), which is an
accepted method for counting
of the IgG4-positive plasma
cells based on Deshpande et al.
[
6
] (c 400×, hematoxylin). The
increased number of
IgG4-positive plasma cells in the salivary
gland (d): 112 IgG4-positive
plasma cells based on the
detailed counting with Cell^D
Program (Olympus, Poland)
Number of patient
Age (years)
Fig. 2 36-year-old female
patient. The characteristic
changes of IgG4-RD (a and b).
It is the typical Mikulicz disease
(MD) with the lacrimal glands
enlargement and salivary glands
enlargement which deformed
normal features. The
improvement after 3 weeks of the
treatment with glucocorticoids
(c and d)
No
Yes
72
Parotid and submandib- Ileus, lacrimal
ular glands, pancreas, glands,
(diabetes mellitus t2),
lymphadperipheral lymphad- enopathy
enopathy
presented in Table 2. The therapy with CS was introduced
in all the cases. In case number three, methotrexate was
added due to the concomitant vasculitis. In case number
five, mycophenolate mofetil was added due to the partial
response to CS therapy and then changed into
methotrexate due to leukopenia.
GPA granulomatosis with polyangiitis, MTX methotrexate, AZA
azathioprine, MMF mycophenolate mofetil, n normal value
Discussion
IgG4-RD belongs to the group of rare diseases. Three major
histopathological features of IgG4-RD are: the
lymphoplasmacytic infiltrates, storiform-type fibrosis of the
irregularly whorled pattern resembling that of a straw mat, and the
obliterative phlebitis. Sometimes the infiltration of
eosinophils is observed in the affected tissues. Some lesions may
be described as pseudotumors as in case number five with
the first clinical presentation of ileus. Necrosis and
granuloma are not found in IgG4-RD. When they are observed, the
rheumatologists should think about the different diagnosis or
alternative disease [
6
]. The diagnostic scheme of IgG4-RD
includes the number of IgG4+ plasma cells in the affected
tissue, and it depends on the localization and the type of
biopsies (a needle biopsy or a surgical specimen) [
6
].
Important is that not all the histopathological features are observed
in all the tissues and the histologically highly suggestive
form of IgG4-RD or the probable features of IgG4-RD are
distinguished [
6
]. The second step of the
histopathological assessment is to determine the ratio of IgG4+ plasma
cells to the general number of IgG cells, which should be
more than 40%, except for the aorta where the ratio should
be more than 50% [
6
]. The differential diagnosis includes
lymphoma, tumor, vasculitis, and abscess and, therefore, the
alternative diseases should be excluded at the beginning of
the assessment. IgG4-RD may mimic the reactive lymphoid
infiltrates and lymphoma, particularly MALT lymphoma.
Both clinically and pathologically, IgG4-RD is manifested
as the mass-forming lesion composed of the dense
lymphoplasmacytic infiltrate [
7–9
]. IgG4-RD with the concomitant
vasculitis, e.g., with GPA as in case number three, is rarely
observed. In this patient, the clinical symptoms were more
severe than in the other patients with the weight loss and
mucosal ulcers in the nose and mouth.
In the non-biopsy-proven cases, e.g., the pancreas or brain
localization, the measurement of the IgG4 concentration in
blood samples is useful. Based on IgG4-RD definition, it
should be elevated above 135 mg/dl [
10
] and it is observed
in most patients. Nevertheless, 20–40% of the patients with
IgG4-RD may have the IgG4 value in the normal ranges.
On the other hand, the increased amount of IgG4 can be
observed in different diseases: the primary Sjögren
syndrome (7%), lupus erythematosus (10%), and rheumatoid
arthritis, cancers and also in the healthy population (2%), but
the criteria of IgG4-RD are fulfilled only by individuals [
10,
11
]. The IgG4 production depended on, among others, Il-10
and Il-6. Among 136 patients with the rheumatoid arthritis,
the increased level of IgG4 in the serum was observed in
46% of patients and was correlated with the active disease
[11].The elevated serum IgG4 levels were the most
important laboratory features of IgG4-RD both in our and other
publications [
12, 13
].The abnormal C3 and C4 complement
levels were not observed in the presented cases, except the
case with vasculitis, and they are not typical for IgG4-RD,
but more frequently appear in other autoimmune disorders.
In one patient we observed eosinophilia, which occurs in
one-third of the patients with IgG4-RD like the allergy
history according to the recent publications [
13
]. Yu Chen et al.
reported a higher frequency of allergic diseases (59%), but
this was not correlated with the increased IgE serum
concentration which was found in 83% of patients. In addition,
the correlation between eosinophilia (33% of patients) and
the allergy history was not observed [
13
]. The history of the
atopic disease included, for example, the bronchial asthma,
allergic rhinitis, nasal polyps, and atopic dermatitis [
14
].
In our group of patients, we did not observe this
correlation between IgG4-RD symptoms and the history of allergic
diseases. The IgE serum concentration was not measured
because it was technically impossible.
The spectrum of IgG4-RD is wide-ranging, occurring
in one or more organs synchronously or metachronously.
Moreover, the patients with IgG4-RD usually do not have
the constitutional symptoms, such as fever, malaise, night
sweats, or the weight loss [
15
]. Malignancies were reported
in 7.4% of patients with IgG4-RD [
16
].The extranodal
marginal zone B cell lymphoma may occur in the ocular area,
salivary glands or the meningeal dura up to 5 years after
the diagnosis of IgG4-RD [
17–19
]. In our cohort, all of the
patients had more than one organ involved. The most
frequent localization was the head and neck area and the parotid
glands. Two patients had the typical Mikulicz disease (MD)
with the lacrimal gland enlargement. The orbital
involvement in IgG4-RD is common and the orbit was the first extra
pancreatic localization to be reported in the literature [
20
].
In the publication, MD was considered to be a subtype of
IgG4-RD. In addition, it had a number of differences
compared to the typical Sjögren syndrome, including not only
the variety of the gender distribution (MD occurs in both
men and women, while Sjögren syndrome occurs mainly in
women) but the normal or mild salivary secretion
dysfunction in MD [
21
]. The symptoms of dryness were not
presented in our cohort and none of the patients met the criteria
for the primary Sjögren syndrome (including the lack of the
specific antibodies and normal salivary flow).
Because of the similarity to Sjögren syndrome (the
lacrimal and salivary glands involvement, case numbers one to
four), the diagnosis of the IgG4-RD was postponed for an
average of 5 years (64 months). Generally, the clinical signs
depended on the localization and organ damage caused by
the main infiltration of IgG4 cells. They often formed
pseudotumors as in patient number five. Nonetheless, the time
for IgG4-RD diagnosis was 17 months late until the patient
was admitted to the Rheumatology Unit. The shortest time
for the diagnosis of IgG4-RD was in the patient with the
unilateral parotid gland enlargement and the concomitant
weight loss. The fast recognition of GPA caused the patient
to be admitted to the Rheumatology Department. The first
suspicion of lymphoma focused the diagnosis on tumor. In
the presented paper, patients had been diagnosed by
specialists in the general medicine, oncologists, surgeons,
endocrinologists, specialists in the travel medicine, and
hematologists before they were admitted to the Rheumatology Unit.
In all the cases, the first diagnoses included the oncological
diseases, e.g., the lacrimal lymphoma, salivary lymphoma,
bowel tumor, lung cancer or hepatoma.
In the presented case series, the Type 1 (IgG4-related)
autoimmune pancreatitis was observed in one patient. It is
one of the most common disease manifestations that often
devolves into the endocrine and exocrine insufficiency
and may complicate the CS treatment. In the described
patient, we started the therapy with CS in the recommended
doses, despite the diabetes mellitus, with the good clinical
response and improvement in the blood glucose level. In
the case number four, the pancreatic biopsy was not
performed because of the technical problem. In the diagnostic
parameters, the IgG4 serum concentration, abdomen
ultrasound, and the computed tomography were used, and the
good clinical improvement after starting the CS treatment
was observed. The diagnosis was ultimately made based on
the classification criteria proposed by the Japanese Pancreas
Society Revision in 2006 and Mayo Clinic [
27–29
].
The anti-nuclear antibodies were detected only in one
case, but in a very low titer, without any specific antibodies,
which is very typical for IgG4-RD compared to other
autoimmune diseases. When the antibodies against the specific
antigenes are present, the concomitant different disease is
the most probable reason. The polyclonal
hypergammaglobulinemia will not help in the diagnostic parameters; it
is typical for Sjögren syndrome, but was often observed in
IgG4-RD too [
12
].
Lymphadenopathy was very common in IgG4-RD
patients, as in the paper of Chen [
13
], and occurred in most
of the patients in the presented article.
In our series, the inflammatory markers ESR and CRP
were elevated in two cases. The results were comparable
with the other authors [
12, 13, 22
], who indicated that
inflammatory factors did not play crucial role in IgG4-RD
pathogenesis and its progression.
In the present study, all the patients were treated with the
oral CS in the dose of prednisone of 0.6 mg/kg of the body
weight/day. The response to this therapy was good, with the
clinical and laboratory improvement. Nevertheless, in the
previous publications, among the patients remaining on the
long-term steroid therapy, the relapse was common after the
cessation of CS [
23
]. Unfortunately, a large percentage of
patients with this condition have the relative
contraindications to the prolonged CS treatment, even in the moderate
to low doses (for example, obesity, the glucose intolerance,
hypertension, and osteoporosis) [
24, 25
]. Other therapies,
such as radiation or the immunomodulating agents, are not
well-described in the literature [26]. The paucity of data
regarding the use of the disease-modifying anti-rheumatic
drugs (DMARDs) provides with a little support for the use
of these medications in the clinical practice, although they
are often used in the hope of reducing the CS dependency.
For this reason, DMARDs were added in patient numbers
three, four, and five due to the partial responsiveness to the
CS therapy. In one case (patient number five), who was
treated with the mycophenolate mofetil, leukopenia was
observed after 2 months of the treatment and the medication
was changed into methotrexate. More recently, the B cell
depletion has shown the evidence of the CS-sparing efficacy
and has even been used as a monotherapy, with considerable
success [
24
], but this therapy option is not commonly
available in Eastern Europe.
There are some limitations of this study. First of all,
there were a small number of patients enrolled only in one
Rheumatology Unit. The time for the diagnosis of
IgG4RD was relatively long. In the presented cases, it was the
mean of 5 years, suggesting that multicenter prospective
study is needed to evaluate the clinical and laboratory
features of IgG4-RD more broadly. Moreover, the benefits of
the diagnostic methods in the diagnosis of IgG4-RD in the
Rheumatology Units should be evaluated in a larger amount
of patients. In our experience, the diagnosis of IgG4-RD
requires the careful clinicopathological correlation. The
diagnosis relies on the coexistence of various clinical,
laboratory, radiological, and histopathological findings, although
none of them is pathognomonic itself. The time needed for
the diagnosis and the variety of clinical forms of IgG4-RD
confirmed that there is a need for the cooperation among
many specialists for the better and earlier recognition of the
disease.
Compliance with ethical standards
Ethical approval For this type of study a formal consent is not
required.
Informed consent The additional informed consent was obtained
from all the individual participants for whom the information
identification is included in this article.
Conflict of interest All authors declare that they have no conflict
of interest.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made.
1. Stone JH , Khosroshahi A , Deshpande V et al ( 2012 ) Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations . Arthritis Rheumatol 64 : 3061 - 3067
2. Takahashi H , Yamamoto M , Suzuki C et al ( 2010 ) The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity . Autoimmun Rev 9 : 591 - 594
3. Umehara H , Okazaki K , Masaki Y et al ( 2011 ) Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD) . Mod Rheumatol 22 : 21 - 30
4. Tanji H , Okada H , Igari R et al ( 2016 ) Inflammatory pseudotumor of the brain parenchyma with IgG4 Hypergammaglobulinemia . Intern Med 55 : 1911 - 1916
5. Gasparyan AY , Ayvazyan L , Blackmore H , Kitas GD ( 2011 ) Writing a narrative biomedical review: considerations for authors, peer reviewers , and editors. Rheumatol Int 31 : 1409 - 1417
6. Deshpande V , Zen Y , Chan JK et al ( 2012 ) Consensus statement on the pathology of IgG4-related disease . Mod Pathol 25 : 181 - 192
7. Karamchandani JR , Younes SF , Warnke RA et al ( 2012 ) IgG4- related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma . Am J Clin Pathol 137 : 699 - 711
8. Lee FJ , Varikatt W , Kairaitis K et al ( 2010 ) IgG4-related dacryoadenitis . Ophthalmology 117 : 398
9. Ohta M , Moriyama M , Goto Y et al ( 2015 ) A case of marginal zone B cell lymphoma mimicking IgG4-related dacryoadenitis and sialoadenitis . World J Surg Oncol 13 : 67
10. Mavragani CP , Fragoulis GE , Rontogianni D et al ( 2014 ) Elevated IgG4 serum levels among primary Sjögren's syndrome patients: do they unmask underlying IgG4-related disease? Arthritis Care Res 66 : 773 - 777
11. Chen LF , Mo YQ , Ma JD et al ( 2014 ) Elevated serum IgG4 defines specific clinical phenotype of rheumatoid arthritis . Med Inflamm. doi: 10 .1155/ 2014 /635293
12. Wallace ZS , Deshpande V , Mattoo H et al ( 2015 ) IgG4-related disease: clinical and laboratory features in one hundred twentyfive patients . Arthritis Rheumatol 67 : 2466 - 2475
13. Chen Y , Zhao JZ , Feng RE et al ( 2016 ) Types of organ involvement in patients with immunoglobulin G4-related Disease . Chin Med J 129 : 1525 - 1532
14. Chen You , Della Torre E , Mattoo H et al ( 2014 ) Prevalence of atopy, eosinophilia, and IgE elevation in IgG4-related disease . Allergy 69 : 269 - 272
15. Yamamoto M , Takahashi H , Shinomura Y ( 2014 ) Mechanisms and assessment of IgG4- related disease: lessons for the rheumatologist . Nat Rev Rheumatol 10 : 148 - 159
16. Yamamoto M , Yajima H , Takahashi H et al ( 2015 ) Everyday clinical practice in IgG4-related dacryoadenitis and/or sialadenitis: results from the SMART database . Mod Rheumatol 25 : 199 - 204
17. Cheuk W , Yuen HK , Chan AC et al ( 2008 ) Ocular adnexal lymphoma associated with IgG4 + chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease . Am J Surg Pathol 32 : 1159 - 1167
18. Oyama T , Takizawa J , Nakamura N et al ( 2011 ) Multifocal mucosa-associated lymphoid tissue lymphoma associated with IgG4-related disease: a case report . J Ophthalmol 55 : 304 - 306
19. Venkataraman G , Rizzo KA , Chavez JJ et al ( 2011 ) Marginal zone lymphomas involving meningeal dura: possible link to IgG4- related diseases . Mod Pathol 24 : 355 - 366
20. Divatia M , Kim SA , Ro JY ( 2012 ) IgG4-related sclerosing disease, an emerging entity: a review of a multi-system disease . Yonsei Med J 53 : 15 - 34
21. Moriyama M , Tanaka A , Maehara T et al ( 2014 ) T helper subsets in Sjögren's syndrome and IgG4-related dacryoadenitis and sialoadenitis: a critical review . J Autoimmun 51 : 81 - 88
22. Deshpande V , Mattoo H , Mahajan VS et al ( 2015 ) IgG4-related disease: clinical and laboratory features in one hundred twentyfive patients . Arthritis Rheumatol 67 : 2466 - 2475
23. Matsushita M , Ikeura T , Fukui T , Uchida K ( 2008 ) Refractory autoimmune pancreatitis: azathioprine or steroid pulse therapy? Am J Gastroenterol 103 : 1834 - 1835
24. Perugino CA , Stone JH ( 2016 ) Treatment of IgG4-related disease . Z Rheumatol 75 : 681 - 686
25. Peng T , Hu Z , Xie T et al ( 2016 ) IgG4-related disease: a case report with duration of more than 16 years and review of literature . Springer Plus 5 : 804
26. Lee CS , Harocopos GJ , Kraus CL et al ( 2015 ) IgG4-associated orbital and ocular inflammation . J Ophthalmic Inflamm Infect 5 : 15
27. Chari ST , Smyrk TC , Levy MJ et al ( 2006 ) Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience . Clin Gastroenterol Hepatol 4 : 1010 - 1016
28. Okazaki K , Kawa S , Kamisawa T et al ( 2006 ) Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal . J Gastroenterol 41 : 626 - 631
29. Chari ST ( 2007 ) Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic HISORt criteria . J Gastroenterol 42 : 39 - 41